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September 16, 2008

Against the Grain: a Celiac Disease Review

by Sam Savage

By Maher, Kevin J

Between 9,000 and 4,000 BC, in the age when glaciers melted and the earth warmed, nomadic hunter-gatherers settled down to more agrarian pursuits and began to cultivate wheat as a source of food. The establishment of this behavior, as it spread from Southeast Asia throughout Europe, is considered to have contributed greatly to mankind's success. The adoption of these new foods, however, was difficult for some. For these individuals and their descendants, a genetic susceptibility and the presence of wheat in the diet caused an inflammatory response in the intestines that lead to malnutrition that would prove fatal for some. In the second century AD, a Greek physician known as Aretaeus of Cappadocia wrote what is thought to be an early description of this illness.1,2 In this account, he referred to a condition involving a number of signs and symptoms, including bellyache that afflicted some children of his time. Some 1,700 years later, these writings were translated to English, and the Greek word for "bellyache" was anglicized to "celiac," which has since been used to describe the condition. Today, we know that celiac disease is an intestinal disorder that affects susceptible individuals when they are exposed to certain cereal grains in the diet.

Celiac disease (CD) - although recognized for some time - was, until recently, considered a relatively rare disease. Through the use of improved testing methods and increased awareness, however, it is now considered to be one of the most common lifelong diseases.3- 9 It is estimated that up to 1% of individuals who are of European descent have intolerance to the grains wheat, barley, and rye, and as many as 3 million people in the United States may be affected.

Susceptibility to celiac disease occurs when a person carries the genes for certain human leukocyte antigens (HLAs).10 The HLAs are cell-surface receptors that normally exhibit a wide range of variation so that they can bind to foreign antigens, such as bacterial or viral proteins, and then present them to T-cells in order to initiate an immune response." In addition to the regular HLAs that recognize the viral and bacterial antigens, celiac patients also have HLAs (named DQ2 and DQ8) that bind to a protein called gliadin, which is found as a component of gluten in certain edible grains. When celiac patients eat foods made from the grains wheat, barley, or rye, some of their HLAs bind to the gliadin protein, and the immune system responds by making antibodies against a number of targets, including gliadin. This inflammatory response causes damage to the intestinal wall, and this interferes with the intestine's ability to absorb nutrients from ingested food. This process of malabsorption, if left untreated, can lead to malnutrition, and patients can develop a variety of signs and symptoms. Infants may present with diarrhea and failure to thrive, while adults may present with iron-deficiency anemia or osteoporosis in the absence of the classic symptoms of diarrhea and abdominal pain.12 For people with celiac disease, the only treatment that is currently available is the permanent avoidance of all sources of gluten. Because most patients who effectively remove gluten from their diet will respond favorably, an accurate and timely diagnosis is of great value.

Diagnosis

The gold standard test for celiac disease is an intestinal biopsy that shows the results of gluten-induced inflammation (e.g., loss of microscopic feathery projections called villi).13,14 But because this procedure is invasive, it is not without risk. For this reason, serologie and molecular tests are often used by physicians to help identify those patients who are most likely to have celiac disease, in order to decide who will get a confirmatory biopsy.13-17

Serologie testing

The first serologie assay developed for celiac disease measured the presence of serum antibodies that bound to gliadin, the alcohol- soluble fraction of gluten. Although these assays were used for more than 20 years, the realization that antigliadin antibodies were often present in people who did not have celiac disease has led to their falling from favor.13,17-20 Improvements in testing came when scientists subsequently identified additional celiac-specific antibodies in the serum that would bind to the membrane surrounding the smooth muscle in slices of monkey esophagus. These endomyseal antibodies (EMAs) are among the most accurate assays for celiac disease. These fluorescence-microscopy-based assays, however, are labor intensive and difficult to standardize.13,21,22 ELISA-based assays that target the enzyme tissue transglutaminase (tTG),23 have since been developed to permit the identification of the EMA reactive antibodies with greater ease and precision. In addition to the improved ease of use, tTG-IgA assays have high sensitivity (- 96%), specificity (-98%), and positive predictive value for identifying those presumptive celiac patients who will go on to have positive intestinal biopsies (-1.00).13

More recently, it has been discovered that antigliadin antibodies from celiac patients specifically recognize gliadin peptides after deamidation.24- 25 This realization has rekindled the interest in antigliadin antibodies, and assays incorporating the deamidated gliadin peptides (DGP) have been shown subsequently to have greater sensitivity and specificity than earlier gliadin assays.20,26-28 Numerous studies have demonstrated that this new generation of gliadin assays have increased accuracy for the diagnosis of CD.26,27- 29 Because the tTG and DGP have different (non-competing) target antigens,30 they can be used together to obtain the best sensitivity without loss of specificity.20

Molecular testing

Another laboratory tool that the clinician has in assessing celiac disease comes from the finding that the risk for CD is genetically linked to specific HLA genes. It is estimated that greater than 98% of all celiac-disease patients express either the DQ2 or DQ8 molecules. If a patient who is suspected of having celiac disease tests negative for the DQ2 and DQ8, then it is unlikely that the patient truly has celiac disease, and the physician should consider other diagnoses.11,17 In contrast, if a patient tests positive for either of these susceptibility markers, they are far from guaranteed to get the disease. In fact, 30% to 40% of healthy individuals without celiac disease also possess these HLA markers, but they never respond to gluten. Because of this, a negative test result is much more informative than a positive result.

Gluten-free diet adherence

The only therapy currently available to treat celiac disease is lifelong removal of gluten from the diet. Following this diet successfully is difficult due to the pervasive nature of gluten. Gluten is a component of many common foods like bread and pasta. Other sources, however, are much more insidious because the presence of gluten is not always indicated on food labels and because it is sometimes a contaminant of other (usually gluten-free) products. Celiac patients who manage to attain complete avoidance of gluten, however, often experience a cessation of the inflammatory response, restoration of intestinal function, and a disappearance of antibodies to both gliadin and tTG. The relationship between the degree of damage in the intestine, the amount of gluten in the diet, and the level of celiac-specific antibodies in the blood allows physicians to use the serologie assays to monitor a patient's disease activity and gauge the level of adherence to the diet.18,19,31

In a study of pediatrie celiac disease, 82% of children were found to be negative for DGP antibodies following their successful adherence to the diet.30 Another celiac-disease antibody that decreases following avoidance of gluten is the antiactin antibody.32,33 These antiactin antibodies, along with antiDGP antibodies, have been demonstrated to correlate with the degree of intestinal damage.20,34 The Celiac Disease Guidelines Committee recommends serologie assessment (e.g., tTG) after six months of treatment with gluten-free diet as an indirect measure of the extent of gluten removal from the diet. Measurement at intervals of one year or longer are suggested to monitor adherence to the diet in the asymptomatic patient13 By following the serologie assays over time, a physician can also document a dietary-induced change in serology to further support diagnosis of celiac disease: If a positive test reverts to negative following a gluten-free diet, or if a negative serology converts to positive following the reintroduction of relevant grains back into the diet, the diagnosis of celiac disease is supported.13

Who should be tested?

Because as much as 1 % of the population is affected, celiac disease should be considered in the differential diagnosis of individuals presenting with persistent diarrhea and poor weight gain, unexplained weight loss, failure to thrive, or other persistent abdominal symptoms such as recurrent abdominal pain, constipation, or vomiting. 13In addition, there are a number of conditions that are associated with greatly elevated incidence of celiac disease; and in these groups, testing should be considered even when the individual may be without symptoms. For instance, 8% of people with type 1 diabetes mellitus have celiac disease, as well as 5% to 12% of Down syndrome, 4% to 8% of Turner's syndrome, 2% to 8% of selective IgA deficiency, and 4.5% of first-degree relatives of celiac patients. Routine testing has been recommended for all children with these conditions once they reach three years of age since negative tests may develop to positives over time.13 Additional considerations

As much as 0.2% of the general population and 10% of celiac patients have an inability to produce antibodies of the IgA class (selective IgA deficiency).17,35,36 This fact has direct consequences regarding the interpretation of serologie test results, since celiac patients who also have selective IgA deficiency will not make IgA antibodies against tTG or any other celiacspecific antigen. Therefore, when a symptomatic patient has negative results for tTG-IgA, DGP-IgA, or EMA-IgA, it could be because they do not have celiac disease or because they have celiac disease but lack the ability to make IgA.

When IgA serologies are negative in a symptomatic patient, measurement of total serum IgA concentration can be useful. Normal total serum IgA levels with negative IgA serologies make the diagnosis of celiac disease less likely. Negative IgA celiac serologies in the context of selective IgA deficiency, however, should prompt further investigation with the use of celiac tests that measure the IgG isotype (e.g., tTG-IgG and DGP-IgG).13 Care should also be taken when evaluating children less than three years old, since a negative test result may be due to the immaturity of the child's immune system.37,38 In this instance, infants with celiac disease will not develop positive celiac serologies until they age.

Finally, successful adherence to a gluten-free diet will often result in a reversion of celiac serology.13,30 In this instance, the lack of celiac-specific antibodies may reflect disease inactivity or a mild form of the disease, but a controlled challenge with gluten may be used to confirm the reappearance of symptoms, mucosal changes, and specific antibody development. Because of the high prevalence of IgA deficiency and the loss of antibodies following a gluten-free diet, the use of multiple assays has been suggested. The coordinated use of assays for tTG-IgA, ITg-IgG, DGP-IGA, and DGP- IgG has been promoted in order to increase the combined diagnostic sensitivity of the assays in select groups and for use as a general screening tool.18,37,38

Conclusion

Celiac disease represents one of the most commonly inherited diseases, but it is thought to be largely underdiagnosed, and many people continue to suffer without a diagnosis or effective treatment. With improved testing, laboratorians stand at the ready to help improve the quality of life for many with this affliction. By correctly identifying those who have celiac disease, healthcare professionals can provide valuable patient education and effective therapy for most who suffer from this ailment. With the power to eliminate the inciting gluten from their diet, most celiac patients can control their disease. Though these measures are effective, this concept is not entirely new. The ancient Greek physician Hypocrites once said, "Let food be thy medicine." In this age, when special diets are promoted for everything from growing hair to preventing cancer, these words still ring true ... particularly for celiac patients.

13. Hill ID, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol NuV. 2005;40(1):1-19.